A number of disease states have been identified as being associated with a cholinergic deficiency or alternatively hyperfunction (Table I). These include central as well as peripheral disorders. Recent studies have indicated that central cholindergic hypofunction may be involved in the pathology of senile dementia of Alzheimer's type (SDAT), and in other neurological and psychiatric disorders as listed in Table I, [A. Fisher and I. Hanin, Life Sci. 27, 1615 (1980); R. Bartus et al, Science 217, 408 (1982)].
TABLE I ______________________________________ THE INVOLVEMENT OF THE CHOLINERGIC NERVOUS SYSTEM IN VARIOUS DISEASE STATES Cholinergic Hypofunction Hyperfunction ______________________________________ Senile Dementia of Alzheimer's Parkinson's Disease Type (SDAT) (1) Pseudo Parkinson's Disease Pick's Disease Spasmodic Torticollis Gerstmann-Straussler Syndrome Depression Down's Syndrome Motion Sickness Huntington's Chorea (1) Friedrich's Ataxia (1) Tardive Dyskinesia (1) Gilles de la Tourette Syndrome (1) Childhood Schizophrenia Anticholinergic Intoxication Anticholinesterase Poisoning Tricyclic Antidepressants Intoxication Myasthenia Gravis Eaton Lambret Syndrome Glaucoma Gastro-Intestinal Tract Gastro-Intestinal Disorders Tract Disorder Urinary Bladder Dysfunction Supranuclear Palsy ______________________________________
Whereas many drugs have been developed for treatment of peripheral cholinergic disorders, drug development for central cholinergic disorders, especially when a cholinergic hypoactivity is implicated, is still at its infancy. Since SDAT appears to be a primary cholinergic hypofunction, trials have been conducted in which ACh precursors (choline- or lecithin), acetylcholinesterase (AChE) inhibitors (physostigmine or tetrahydroaminoacridine), or direct acting agonists (arecoline) have been administered to SDAT patients because of the ability of these agents to elevate cholinergic activity in the brain. Although the results have not been conclusive as to the efficiency to the treatment with the above mentioned agents, some encouraging results were obtained with AChE inhibitors and direct acting agonists.
Unfortunately, some of these drugs, such as physostigmine, exhibit a short-half life, due to rapid metabolism following systemic administration. Moreover, physostigmine and some other cholinergic drugs, have a narrow therapeutic window (i.e. ratio between the medium toxic dose and the medium effective dose), and cause side effects which limit their systematic use. Some of the mentioned disorders require chronic treatment and thus the issue of side effects is critical.
Recently, physostigmine has been formulated for oral dosage in tablets. The almost inevitable result of oral administration of drugs is that the level of the drug in circulation surges to a high, each time the drug is administered, followed by a gradual decline in concentration in the blood and body.
A plot of drug concentration in blood following a dosage schedule of several tablets a day has the appearance of a series of peaks, which may surpass the toxic threshold, and minima which may be below the effective dose. To obtain the desired therapeutic effect, it is necessary to establish a dosage regime of multiple unit doses over a 24-hour period. This regime is of particular problem when dealing with demented patients, like SDAT patients.
Administration of cholinergic drugs by other routes, such as injection is inconvenient, painful, and due to their short life in the body, not practical, especially when there is a need for repeated injections.
One way to avoid the problems mentioned above is to administer systemically active drugs through the skin. The percutaneous route has attributes that are superior to other modes of systemic drug administration:
(1) It alllows a continuous administration of the drug to the circulation over a prolonged period of time; PA0 (2) It provides an essentially stable drug level in the blood, thus limiting side effects due to overdosing, and lack of effect due to underdosing; PA0 (3) It permits use of pharmacologically active agents with a short biological half life; PA0 (4) It simplifies the medication regimen.
Despite these advantages, the transdermal mode of administration has not been widely used. Recently, however, a few transdermal delivery systems were developed. These include the transdermal delivery systems for scopolamine and for nitroglycerine (Chemical Week, September 26, 1984, P. 42).
The transdermal delivery of systemically active drugs through the skin has certain constraints which limit its wider application. The main one is the need for very potent drugs, since the skin represents a partial barrier to the passage of many substances. Thus, the most suitable drugs for controlled administration via this route, are those active at a parenteral dose of a few mgs per day or less.
Many cholinergic and anticholinergic drugs are effective at this dose range.